PROJECT SUMMARY/ABSTRACT L1CAMs are a family of immunoglobulin cell adhesion molecules that play important roles in the development of nervous system, including axon guidance and morphogenesis as well as axon myelination. Mutations in L1CAMs are directly linked to the neurological L1 syndrome, the symptoms of which include mental retardation and hydrocephalus. In addition, L1CAMs are implicated in neurosychiatric disorders, including schizophrenia, the autistic spectrum disorder, and addiction. One salient feature of L1CAM-associated diseases is that they are heterogeneous and genetically complex and subject to genetic modification, pointing to the existence of as-yet-unidentified functions for L1CAMs that are likely masked by genetic compensatory mechanisms. As transmembrane proteins, L1CAMs sit on the plasma membrane and thus are primed to integrate extracellular signals, converting them into cellular responses that require cross-talk with the cytoskeletal and intracellular signaling networks. Molecular mechanisms by which cell adhesion receptors relay these signals are just beginning to be uncovered, but much is still unknown. This application seeks to fill these gaps, identifying previously- uncharacterized L1CAM functions in synaptic regulation and defining the molecular mechanisms by which L1CAMs are functionally linked to intracellular signaling networks. We have established C. elegans as a powerful genetic system to dissect the roles and mechanisms of L1CAMs. In our previous studies, we determined that the C. elegans L1CAMs, SAX-7 LAD-2 function in maintaining nervous system integrity and axon guidance respectively. We have made significant inroads into defining L1CAM mechanisms of action that are remarkably conserved between mammals and C. elegans. Our recent studies, which took advantage of the ability to easily conduct modifier screens in C. elegans, identified the interplay between the mitogen-activated protein kinase (MAPK) signaling cascade and L1CAMs in an unexpected role in synaptic regulation. To better define the molecular mechanisms that link L1CAMs and MAPK to the synaptic machinery, our aims are 1) to define the roles of SAX-7 and MAPK in the synaptic vesicle cycle, 2) to resolve how SAX-7 and MAPK-1 coordinately regulate synaptic function, and 3) to define the factors that mediate SAX-7 and MAPK roles in synaptic transmission. With L1CAMs and MAPK implicated in both intellectual disability and the autism spectrum, this basic research in C. elegans will reveal fundamental knowledge on synaptic modulation that will provide additional insight into mechanisms underlying human neuropsychiatric disorders.